Publications

Mammalian olfaction and reproduction are tightly linked, a link less explored in humans. Here, we asked whether human unexplained repeated pregnancy loss (uRPL) is associated with altered olfaction, and particularly altered olfactory responses to body-odor. We found that whereas most women with uRPL could identify the body-odor of their spouse, most control women could not. Moreover, women with uRPL rated the perceptual attributes of men’s body-odor differently from controls. These pronounced differences were accompanied by an only modest albeit significant advantage in ordinary, non-body-odor-related olfaction in uRPL. Next, using structural and functional brain imaging, we found that in comparison to controls, most women with uRPL had smaller olfactory bulbs, yet increased hypothalamic response in association with men’s body-odor. These findings combine to suggest altered olfactory perceptual and brain responses in women experiencing uRPL, particularly in relation to men’s body-odor. Whether this link has any causal aspects to it remains to be explored.

All primates, including humans, engage in self-face-touching at very high frequency. The functional purpose or antecedents of this behaviour remain unclear. In this hybrid review, we put forth the hypothesis that self-face-touching subserves self-smelling. We first review data implying that humans touch their faces at very high frequency. We then detail evidence from the one study that implicated an olfactory origin for this behaviour: This evidence consists of significantly increased nasal inhalation concurrent with self-face-touching, and predictable increases or decreases in self-face-touching as a function of subliminal odourant tainting. Although we speculate that self-smelling through self-face-touching is largely an unconscious act, we note that in addition, humans also consciously smell themselves at high frequency. To verify this added statement, we administered an online self-report questionnaire. Upon being asked, approximately 94% of approximately 400 respondents acknowledged engaging in smelling themselves. Paradoxically, we observe that although this very prevalent behaviour of self-smelling is of concern to individuals, especially to parents of children overtly exhibiting self-smelling, the behaviour has nearly no traction in the medical or psychological literature. We suggest psychological and cultural explanations for this paradox, and end in suggesting that human self-smelling become a formal topic of investigation in the study of human social olfaction. This article is part of the Theo Murphy meeting issue 'Olfactory communication in humans'.

After severe brain injury, it can be difficult to determine the state of consciousness of a patient, to determine whether the patient is unresponsive or perhaps minimally conscious(1), and to predict whether they will recover. These diagnoses and prognoses are crucial, as they determine therapeutic strategies such as pain management, and can underlie end-of-life decisions(2,3). Nevertheless, there is an error rate of up to 40% in determining the state of consciousness in patients with brain injuries(4,5). Olfaction relies on brain structures that are involved in the basic mechanisms of arousal(6), and we therefore hypothesized that it may serve as a biomarker for consciousness(7). Here we use a non-verbal non-task-dependent measure known as the sniff response(8-11) to determine consciousness in patients with brain injuries. By measuring odorant-dependent sniffing, we gain a sensitive measure of olfactory function(10-15). We measured the sniff response repeatedly over time in patients with severe brain injuries and found that sniff responses significantly discriminated between unresponsive and minimally conscious states at the group level. Notably, at the single-patient level, if an unresponsive patient had a sniff response, this assured future regaining of consciousness. In addition, olfactory sniff responses were associated with long-term survival rates. These results highlight the importance of olfaction in human brain function, and provide an accessible tool that signals consciousness and recovery in patients with brain injuries.

Olfactory stimulus acquisition is perfectly synchronized with inhalation, which tunes neuronal ensembles for incoming information. Because olfaction is an ancient sensory system that provided a template for brain evolution, we hypothesized that this link persisted, and therefore nasal inhalations may also tune the brain for acquisition of non-olfactory information. To test this, we measured nasal airflow and electroencephalography during various non-olfactory cognitive tasks. We observed that participants spontaneously inhale at non-olfactory cognitive task onset and that such inhalations shift brain functional network architecture. Concentrating on visuospatial perception, we observed that nasal inhalation drove increased task-related brain activity in specific task-related brain regions and resulted in improved performance accuracy in the visuospatial task. Thus, mental processes with no link to olfaction are nevertheless phase-locked with nasal inhalation, consistent with the notion of an olfaction-based template in the evolution of human brain function.

As far as I know, the only reason we need to sleep that is really, really solid is because we get sleepy. Coming from William C. Dement, one of the pioneers of contemporary sleep research, this statement depicts sleep as a neurobiological black box. One of the best ways to probe such black boxes is through exceptions, and olfaction stands out as such an exceptional sensory system during sleep. Specifically, whereas sensory stimuli presented during sleep typically wake, this is not the case with odors. In fact, odors may promote sleep. In turn, they remain processed by the sleeping brain, and provide a telling window onto sleeping brain capabilities. Here, we briefly review the foundations of sleep, and then extensively detail the literature on olfaction in sleep, concentrating on studies in humans. We speculate that the unique interplay of sleep and smell whereby odors are processed in sleep without causing wake reflects unique aspects of olfactory neurophysiology, particularly the direct projections from periphery to cortex without a thalamic relay. Finally, although the mechanisms allowing odor processing during sleep without arousal remain unclear, this phenomenon lends itself to using olfaction as a window onto sleep mentation. This approach has uncovered several aspects of learning and memory during sleep. We review these efforts, and conclude with detailing their potential application in the treatment of disease.

Nasal airflow is greater in one nostril than in the other because of transient asymmetric nasal passage obstruction by erectile tissue. The extent of obstruction alternates across nostrils with periodicity referred to as the nasal cycle. The nasal cycle is related to autonomic arousal and is indicative of asymmetry in brain function. Moreover, alterations in nasal cycle periodicity have been linked to various diseases. There is therefore need for a tool allowing continuous accurate measurement and recording of airflow in each nostril separately. Here we provide detailed instructions for constructing such a tool at minimal cost and effort. We demonstrate application of the tool in 33 right-handed healthy subjects, and derive several statistical measures for nasal cycle characterization. Using these measures applied to 24-hour recordings we observed that: 1: subjects spent slightly longer in left over right nostril dominance (left = 2.63 +/- 0.89 hours, right = 2.17 +/- 0.89 hours, t(32) = 2.07, p <0.05), 2: cycle duration was shorter in wake than in sleep (wake = 2.02 +/- 1.7 hours, sleep = 4.5 +/- 1.7 hours, (t(30) = 5.73, p <0.0001). 3: slower breathing was associated with a more powerful cycle (the extent of difference across nostrils) (r = 0.4, p <0.0001), and 4: the cycle was influenced by body posture such that lying on one side was associated with greater flow in the contralateral nostril (p <0.002). Finally, we provide evidence for an airflow cycle in each nostril alone. These results provide characterization of an easily obtained measure that may have diagnostic implications for neurological disease and cognitive state.

Each person expresses a potentially unique subset of similar to 400 different olfactory receptor subtypes. Given that the receptors we express partially determine the odors we smell, it follows that each person may have a unique nose; to capture this, we devised a sensitive test of olfactory perception we termed the "olfactory fingerprint." Olfactory fingerprints relied on matrices of perceived odorant similarity derived from descriptors applied to the odorants. We initially fingerprinted 89 individuals using 28 odors and 54 descriptors. We found that each person had a unique olfactory fingerprint (P <10(-10)), which was odor specific but descriptor independent. We could identify individuals from this pool using randomly selected sets of 7 odors and 11 descriptors alone. Extrapolating from this data, we determined that using 34 odors and 35 descriptors we could individually identify each of the 7 billion people on earth. Olfactory perception, however, fluctuates over time, calling into question our proposed perceptual readout of presumably stable genetic makeup. To test whether fingerprints remain informative despite this temporal fluctuation, building on the linkage between olfactory receptors and HLA, we hypothesized that olfactory perception may relate to HLA. We obtained olfactory fingerprints and HLA typing for 130 individuals, and found that olfactory fingerprint matching using only four odorants was significantly related to HLA matching (P <10(-4)), such that olfactory fingerprints can save 32% of HLA tests in a population screen (P <10(-6)). In conclusion, a precise measure of olfactory perception reveals meaningful nonolfactory genetic information.

Recent findings suggest that novel associations can be learned during sleep. However, whether associative learning during sleep can alter later waking behavior and whether such behavioral changes last for minutes, hours, or days remain unknown. We tested the hypothesis that olfactory aversive conditioning during sleep will alter cigarette-smoking behavior during ensuing wakefulness. A total of 66 human subjects wishing to quit smoking participated in the study (23 females; mean age, 28.7 +/- 5.2 years). Subjects completed a daily smoking diary detailing the number of cigarettes smoked during 7 d before and following a 1 d or night protocol of conditioning between cigarette odor and profoundly unpleasant odors. We observed significant reductions in the number of cigarettes smoked following olfactory aversive conditioning during stage 2 and rapid eye movement (REM) sleep but not following aversive conditioning during wakefulness (p <0.05). Moreover, the reduction in smoking following aversive conditioning during stage 2 (34.4 +/- 30.1%) was greater and longer lasting compared with the reduction following aversive conditioning during REM (11.9 +/- 19.2%, p <0.05). Finally, the reduction in smoking following aversive conditioning during sleep was significantly greater than in two separate control sleep experiments that tested aversive odors alone and the effects of cigarette odors and aversive odors without pairing. To conclude, a single night of olfactory aversive conditioning during sleep significantly reduced cigarette-smoking behavior in a sleep stage-dependent manner, and this effect persisted for several days.

Ample evidence suggests that social chemosignaling plays a significant role in human behavior. Processing of odors and chemosignals depends on sniffing. Given this, we hypothesized that humans may have evolved an automatic mechanism driving sniffs in response to conspecific sniffing. To test this, we measured sniffing behavior of human subjects watching the movie Perfume, which contains many olfactory sniffing events. Despite the total absence of odor, observers sniffed when characters in the movie sniffed. Moreover, this effect was most pronounced in scenes where subjects heard the sniff but did not see the sniffed-at object. We liken this response to the orienting towards conspecific gaze in vision and argue that its robustness further highlights the significance of olfactory information processing in human behavior.

Animal studies of discriminative fear conditioning traditionally use stimuli that are distant in physical features and thus easily distinguished perceptually. Independently, human studies have shown that training mostly improves discrimination thresholds. We found that aversive learning actually induced an increase in discrimination thresholds in humans and that subjective aversion during conditioning predicted the individual threshold change. This counterintuitive performance deterioration occurred when using odors or sounds as aversive reinforcers and was not a result of attentional distraction or decision bias. In contrast, positive reinforcement or mere exposure induced the typically reported decrease in thresholds. Our findings indicate that aversive outcomes induce wider stimulus generalization by modulating perceptual thresholds, suggesting the engagement of low-level mechanisms. We suggest that for risk- or loss-related stimuli, less specificity could be a benefit, as it invokes the same mechanisms that respond quickly and efficiently in the face of danger.

The mammalian brain commonly uses structural proximity to reflect proximity in stimulus and perceptual space. Objects or object features that are near each other in physical structure or perception are also near each other in the brain. This generates sensory maps. The topography of olfactory connectivity implies a rudimentary map in the olfactory epithelium, a more intricate map in the olfactory bulb, but no ordered topography is evident in piriform cortex. Currently, we are largely unable to link the ordered topography in epithelium and bulb to meaningful olfactory axes within a strong predictive framework. We argue that the path to uncovering such a predictive framework depends on systematically characterizing olfactory perception, and we describe initial efforts in this direction.

Paradoxically, although humans have a superb sense of smell, they don't trust their nose. Furthermore, although human odorant detection thresholds are very low, only unusually high odorant concentrations spontaneously shift our attention to olfaction. Here we suggest that this lack of olfactory awareness reflects the nature of olfactory attention that is shaped by the spatial and temporal envelopes of olfaction. Regarding the spatial envelope, selective attention is allocated in space. Humans direct an attentional spotlight within spatial coordinates in both vision and audition. Human olfactory spatial abilities are minimal. Thus, with no olfactory space, there is no arena for olfactory selective attention. Regarding the temporal envelope, whereas vision and audition consist of nearly continuous input, olfactory input is discreet, made of sniffs widely separated in time. If similar temporal breaks are artificially introduced to vision and audition, they induce "change blindness", a loss of attentional capture that results in a lack of awareness to change. Whereas "change blindness" is an aberration of vision and audition, the long inter-sniff-interval renders "change anosmia" the norm in human olfaction. Therefore, attentional capture in olfaction is minimal, as is human olfactory awareness. All this, however, does not diminish the role of olfaction through sub-attentive mechanisms allowing subliminal smells a profound influence on human behavior and perception.

Odor identity is coded in spatiotemporal patterns of neural activity in the olfactory bulb. Here we asked whether meaningful olfactory information could also be read from the global olfactory neural population response. We applied standard statistical methods of dimensionality-reduction to neural activity from 12 previously published studies using seven different species. Four studies reported olfactory receptor activity, seven reported glomerulus activity, and one reported the activity of projection-neurons. We found two linear axes of neural population activity that accounted for more than half of the variance in neural response across species. The first axis was correlated with the total sum of odor-induced neural activity, and reflected the behavior of approach or withdrawal in animals, and odorant pleasantness in humans. The second and orthogonal axis reflected odorant toxicity across species. We conclude that in parallel with spatiotemporal pattern coding, the olfactory system can use simple global computations to read vital olfactory information from the neural population response.

A primary goal for artificial nose (eNose) technology is to report perceptual qualities of novel odors. Currently, however, eNoses primarily detect and discriminate between odorants they previously "learned''. We tuned an eNose to human odor pleasantness estimates. We then used the eNose to predict the pleasantness of novel odorants, and tested these predictions in naive subjects who had not participated in the tuning procedure. We found that our apparatus generated odorant pleasantness ratings with above 80% similarity to average human ratings, and with above 90% accuracy at discriminating between categorically pleasant or unpleasant odorants. Similar results were obtained in two cultures, native Israeli and native Ethiopian, without retuning of the apparatus. These findings suggest that unlike in vision and audition, in olfaction there is a systematic predictable link between stimulus structure and stimulus pleasantness. This goes in contrast to the popular notion that odorant pleasantness is completely subjective, and may provide a new method for odor screening and environmental monitoring, as well as a critical building block for digital transmission of smell.

To assess the feasibility of using odors as a potential mechanism for treating sleep apnea, we set out to test the hypothesis that odorants delivered during sleep would modify respiratory patterns without inducing arousal or wake in healthy sleepers. We used 2 mildly trigeminal odorants: the pleasant lavender and unpleasant vetiver oil and 2 pure olfactory odorants: the pleasant vanillin and unpleasant ammonium sulfide. During sleep, an olfactometer delivered a transient odorant every 9,12, or 15 min (randomized), providing 21-37 odorant presentations per night. Each of 36 participants was studied for 1 night and with 1 of the 4 different odorants tested. In addition to standard overnight polysomnography, we employed highly accurate measurements of nasal and oral respiration. Odorants did not increase the frequency of arousals or wake but did influence respiration. Specifically, all 4 odorants transiently decreased inhalation and increased exhalation for up to 6 breaths following odor onset. This effect persisted regardless of odorant valence or stage of sleep. These results suggest that the olfactory system may provide a path to manipulate respiration in sleep.

LElectroolfactograms (EOGs) are the summated generator potentials of olfactory receptor neurons measured directly from the olfactory epithelium. To validate the sensory origin of the human EOG, we set out to ask whether EOGs measured in humans were odorant concentration dependent. Each of 22 subjects (12 women, mean age = 23.3 yr) was tested with two odorants, either valeric acid and linalool (n = 12) or isovaleric acid and l-carvone (n = 10), each delivered at four concentrations diluted with warm (37°C) and humidified (80%) odorless air. In behavior, increased odorant concentration was associated with increased perceived intensity (all F > 5, all P < 0.001). In EOG, increased odorant concentration was associated with increased area under the EOG curve (all F > 8, all P < 0.001). These findings substantiate EOG as a tool for probing olfactory coding directly at the level of olfactory receptor neurons in humans.

Whereas the rules underlying the perceived intensity of binary mixtures have been investigated, minimal efforts have been directed at elucidating the rules underlying the perceived pleasantness of such mixtures. To address this, 84 subjects ranked the pleasantness and intensity of 5 distinct binary mixtures (15 pairs, inter-stimulus interval = 4 s, inter-trial interval = 30 s, flow = 6 l/min, pulse = 2 s) constructed from different ratios (0:100%, 25:75%, 50:50%, 75:25%, and 100:0%, olfactometer-generated vapor phase). We found that in the majority of cases, the pleasantness of the mixture fell between the pleasantness values of its separated constituents and that it was strongly influenced by the relative intensities of the constituents. Based on these results, we proposed a prediction paradigm for the pleasantness of binary mixtures from the pleasantness of their separated constituents weighted by their respective perceived intensities. The uniqueness of the proposed paradigm is that it neither requires presetting an interaction constant between the mixture components nor require any factorization of the pleasantness weights. It does, nonetheless, require solid psychophysical data on the separated components at their different concentrations, and currently it can only explain the behavior of intermediate pleasantness of mixtures.

In studies of vision and audition, stimuli can be systematically varied by wavelength and frequency, respectively, but there is no equivalent metric for olfaction. Restricted odorant-feature metrics such as number of carbons and functional group do not account for response patterns to odorants varying along other structural dimensions. We generated a multidimensional odor metric, in which each odorant molecule was represented as a vector of 1,664 molecular descriptor values. Revisiting many studies, we found that this metric and a second optimized metric were always better at accounting for neural responses than the specific metric used in each study. These metrics were applicable across studies that differed in the animals studied, the type of olfactory neurons tested, the odorants applied and the recording methods used. We use this new metric to recommend sets of odorants that span the physicochemical space for use in olfaction experiments.

Although it is agreed that physicochemical features of molecules determine their perceived odor, the rules governing this relationship remain unknown. A significant obstacle to such understanding is the high dimensionality of features describing both percepts and molecules. We applied a statistical method to reduce dimensionality in both odor percepts and physicochemical descriptors for a large set of molecules. We found that the primary axis of perception was odor pleasantness, and critically, that the primary axis of physicochemical properties reflected the primary axis of olfactory perception. This allowed us to predict the pleasantness of novel molecules by their physicochemical properties alone. Olfactory perception is strongly shaped by experience and learning. However, our findings suggest that olfactory pleasantness is also partially innate, corresponding to a natural axis of maximal discriminability among biologically relevant molecules.

We provide detailed instructions and part selections for construction of a five-channel air dilution olfactometer capable of generating neat odorants and binary mixtures at a range of known concentrations. At the heart of the olfactometer is an odorant canister that is (1) cheap and readily available, (2) safe and durable, (3) has minimal odor adherence, (4) is easily incorporated into any olfactometer, and critically (5) produces a highly consistent stimulus. By flowing a given carrier gas at a given flowrate through a given odorant in this canister, the same end-vapor is achieved. Flow/concentration outcomes are provided for several odorants routinely used in olfactometry. This toot will enable researchers to generate known concentrations without expensive analytical machinery. 

Rodents use chemosignals to alter endocrine balance in conspecifics. Although responses to human sweat suggest a similar mechanism in humans, no particular component of human sweat capable of altering endocrine balance in conspecifics has yet been isolated and identified. Here, we measured salivary levels of the hormone cortisol in women after smelling pure androstadienone (4,16-androstadien-3-one), a molecule present in the sweat of men that has been suggested as a chemosignal in humans. We found that merely smelling androstadienone maintained significantly higher levels of the hormone cortisol in women. These results suggest that, like rodents, humans can influence the hormonal balance of conspecifics through chemosignals. Critically, this study identified a single component of sweat, androstadienone, as capable of exerting such influence. This result points to a potential role for synthetic human chemosignals in clinical applications.

Forty years ago, von Bekesy demonstrated that the spatial source of an odorant is determined by comparing input across nostrils, but it is unknown how this comparison is effected in the brain. To address this, we delivered odorants to the left or right of the nose, and contrasted olfactory left versus right localization with olfactory identification during brain imaging. We found nostril-specific responses in primary olfactory cortex that were predictive of the accuracy of left versus right localization, thus providing a neural substrate for the behavior described by von Bdkdsy. Additionally, left versus right localization preferentially engaged a portion of the superior temporal gyrus previously implicated in visual and auditory localization, suggesting that localization information extracted from smell was then processed in a convergent brain system for spatial representation of multisensory inputs.

There are large individual differences in the self-reported ability to form vivid olfactory mental imagery. Based on such self-reports, subjects have been classified as 'bad' or 'good' imagers. The present study examined whether a differential strategy in re-enacting the olfactomotor response during imagery may explain the dissociation between 'bad' and 'good' olfactory imagers. As previously reported, odor imagery was accompanied by sniffing. Although 'bad' and 'good' olfactory imagers did not differ in their overall sniffing volume, they used different strategies when re-enacting the motor component of olfaction during imagery. Particularly, as in real perception, 'good' but not 'bad' imagers generated bigger sniffs when imagining a pleasant smell compared with an unpleasant smell (P <0.02). Furthermore, preventing sniffing significantly hampered mental imagery of pleasant odors in 'good' but not 'bad' imagers (P <0.03). Taken together, these results suggest (i) the validity of the dissociation between 'bad' and 'good' olfactory imagers as revealed by self-report; (ii) that sniffing may be a causal factor in the creation of olfactory imagery; and (iii) that sniff measurements may serve as a reliable non-verbal tool in exploring individual differences in odor imagery.

The effects of sniffing different concentrations of the human sex-steroid derived compound 4,16-androstadien-3-one (AND) on autonomic nervous system function and mood were measured in 60 subjects. The effects were sex-specific and concentration-dependent. Only high concentrations of AND (0.00625 M) increased positive mood (p <0.03) and decreased negative mood (p <0.05) in women compared to men, and had sympathetic-like effects in women (p <0.003), and parasympathetic-like effects in men (p <0.05). These findings further implicate AND in chemical communication between humans, but pose questions as to the path by which AND is transduced, whether through chemical sensing or transdermal diffusion. 

Neural representations created in the absence of external sensory stimuli are referred to as imagery(1), and such representations may be augmented by reenactment of sensorimotor processes(2). We measured nasal airflow in human subjects while they imagined sights, sounds and smells, and only during olfactory imagery did subjects spontaneously enact the motor component of olfaction-that is, they sniffed. Moreover, as in perception(3,4), imagery of pleasant odors involved larger sniffs than imagery of unpleasant odors, suggesting that the act of sniffing has a functional role in creating of olfactory percepts.

Sniffs are modulated in response to odor content. Higher concentrations of odor induce lesser-volume sniffs. This phenomenon implicates a neural feedback mechanism that measures sensory input (odor concentration) and modulates motor output (sniffing) accordingly. Here we used air-dilution olfactometry to probe the time course of this olfactomotor mechanism. A stainless-steel computer-controlled olfactometer, equipped with mass flow controllers, temperature and humidity control, and on-line photo-ionization detection, was coupled to a highly sensitive pneumatotachograph that measured nasal flow. The olfactometer was used to generate four ascending concentrations of the odorants propionic acid and phenethyl alcohol. Sniff volume was inversely related to odor concentration (P <0.0001). Sniffs were uniform and concentration independent for the initial 150 ms but acquired a concentration-dependent flowrate as early as 160 ms following sniff onset for propionic acid (P <0.05) and 260 ms for phenethyl alcohol (P <0.05). Considering that odorant transduction takes around 150 ms and odorant-induced cortical evoked potentials have latencies of around 300 ms, the rapid motor adjustments measured here suggest that olfactomotor sniff feedback control is subcortical and may rely on neural mechanisms similar to those that modulate eye movements to accommodate vision and ear movements to accommodate audition.